CH641185A5 - ACID ADDITIONAL SALTS RIGHT-ROTATING ERGOT ALKALOIDS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS. - Google Patents

Description

The present invention relates to acid addition salts of right-handed ergot alkaloids, a process for their preparation and medicaments which contain the acid addition salts mentioned.

The present invention relates to acid addition salts of ergotaminin, ergosinin, ergocryptinin, ergocristinin and ergocorninin of the general formula

I-

OH

MM ^ ^

where Ri and R2

with Ergotaminin with Ergosinin with Ergokryprinin with Ergocristinin with Ergocorninin

Ri

R2

-CH3

-CH3

-cfT "" 0

H3

-eleven

CH3 • CK} -CH 3

-CThCóHj

-CH2C

-CHzCH

-CH2C6H5

-cu- ""

CH3

-CH3

-CH3

mean,

which are suitable for the treatment of arterial hypertension, heart failure, cardiac arrhythmia and migraines.

Ergotaminin, Ergosinin, Ergokryptinin, Ergocristinin and Ergocorninin differ from the natural left-turning Ergot alkaloids by the configuration at the 8-position. They arise from the epimerization of natural alkaloids (A. Hofmann, Die ergot alkaloids, F. Enke Verlag, Stuttgart 1964, pp. 20-30). They are derivatives of (5R, 8S) -Lysergic or D-Isolysergic acid.

J.

- H,

J =

CHa

0

(1)

So far, they have not been considered pharmacologically active and therefore, in contrast to the left-turning isomers ergotamine, ergosin, ergocryptin, ergocristin and ergocornin, 40 which are derivatives of lysergic acid, are not considered therapeutically usable.

The consequence of this fact is that in the patent literature and in the other literature numerous methods for the isolation of left-turning isomers, which are used in medicine in large quantities, are described, but in this literature no methods for the isolation of those so far have not been described right-handed isomers used can be found. So far, only processes for converting the two isomeric forms into one another by heating in methanol or by forming insoluble salts have been published; however, these methods can only be used for scientific purposes (Stoll, A., Hofmann, A., Helv. chim. acta 28, 1943, 1570; Stoll, A., Helv. chim. acta 28, 1945, 1283; Hofmann, A ., The ergot alkaloids, Stuttgart 1964, Ferdinand Enke Verlag).

Fresh ergot contains only very small amounts of clockwise isomer. Something more can be found in the drug that has been stored for some time. Since both isomeric forms 60 are reversible and easily merge, right-rotating isomers are formed during the production process, despite various measures that should prevent this merging. Ergotaminin, ergosinin, ergocryptinin, ergocristinin and ergocor-65 ninin reach their highest concentration in the crystallization lyes remaining after the crystallization of their left-turning isomers, in which their proportion is 50 to 80%. In addition to the alkaloids, these also contain alkalis

55

3rd

641185

considerable amounts of colored fiber and decomposition products.

In Yugoslav patent application No. P 1465/78, a process for the isolation of pure ergotaminin, ergosinin, ergocryptinin, ergocristinin and ergocorninin from the crystallization lyes remaining after the crystallization of their left-turning isomers is described, which is characterized in that dried crystallization liquors in a Dissolve ten times the amount of methylene chloride and in a ratio of 1: 100 of neutral aluminum oxide (activity III-IV according to Brockmann) using a methylene chloride / n-propanol mixture 100: 0.2 to 1.4 vol / vol chromatographs.

This creates the possibility of producing right-handed isomers on an industrial scale and their use in therapy.

Since right-handed ergot alkaloids are sparingly soluble in water and as such unsuitable for therapeutic use, they are converted into their physiologically tolerated acid addition salts for this purpose. The biological efficacy of right-handed Ergot alkaloids can be described as extremely surprising, since until now it has been generally accepted that these Ergot alkaloids are biologically ineffective (Goodman, L. and Gilman, A., The Pharmacological Basis of Therapeutics, 5th edition, New York 1975; Stadler, PA and Stütz, P., The Alkaloids, Vol. XV, The Ergot Alkaloids, Chemistry and Physiology 1975, Academic Press, New York, pp. 30 et seq.) And that they do not use acids at all form stable salts (The Merck Index, 9th edition, Merck & Co., Inc., 1976, pp. 476,477 and 479; A. Hofmann, Die Mutterkornalkaloide, F. Enke Verlag, Stuttgart 1964, pp. 21-28).

However, it has now been found that acid addition salts of right-handed ergot alkaloids ergotaminin, ergosinin, ergocryptinin, ergocristinin and ergocorninin are produced according to the invention by the fact that the right-handed ergot alkaloid is used in a solvent which is inert to the reactants, and which per mole of the right-handed ergot -Alkaloids contains 1 to 1.7 mol of the desired inorganic or organic acid, dissolves and the acid addition salt is eliminated by adding a precipitation solvent.

An alkanol having 1 to 3 carbon atoms or a ketone having 3 to 6 carbon atoms is preferably used as the solvent which is inert to the reactants.

An aliphatic ether having 4 to 8 carbon atoms is preferably used as the precipitation solvent.

A strong inorganic or a strong organic acid with a physiologically acceptable anion can be used as the acid. Examples of inorganic acids include Hydrochloric acid, hydrobromic acid, nitric acid, as organic acids e.g. Methanesulfonic acid, ethanesulfonic acid, haloacetic acids, e.g. Trichloroacetic acid, trifluoroacetic acid, etc. in question.

As already mentioned, the acid addition salts of so-called right-handed ergot alkaloids have interesting pharmacological properties, which are listed below.

1. Acute toxicity

The mean lethal dose LD 50 during intraperitoneal administration was determined in male mice with a body weight of 18 to 25 g. The volume of the injected solution was 0.01 ml / g body weight. Table I summarizes acute toxicities of right-handed Ergot alkaloids compared to the left-handed Ergot alkaloids after 24 hours of intraperitoneal application.

Table I

substance

LDso (mg / kg)

Ergotaminin methanesulfonate

> 300

Ergosinin methanesulfonate

244.7 ++

Ergocryptinine methanesulfonate

> 520

Ergocristinin methanesulfonate

> 600

Ergocorninine methanesulfonate

> 520

Ergotamine tartrate

412.0 (322.4 to 626.5) +

Ergosine methanesulfonate

206.3 (158.2 to 268.9) +

Ergocryptine methanesulfonate

187.9 ++

Ergocristine methanesulfonate

234.0 (123.0 to 44.6) +

+ determined using the method of Litchfield, J. and Wilcoxon,

F., J. Pharmacol. exp. Therapist 96 (1949), 99.

+ + determined according to the method by Körber, G., Arch. exp. path. Pharmacol.

162 (1931) 480.

These results indicate that right-handed Ergot alkaloids are less toxic than left-handed Ergot alkaloids.

2. Effect on arterial blood pressure a) Effect on blood pressure and pulse of normotensive anesthetized rats

Wistar rats were anesthetized, the common carotid artery was cannulated and the blood pressure was recorded using a mini transducer on a dynograph (Beckmann type). The pulse rate was recorded on the same dynograph using a cardiotachometer. Right-turning ergot alkaloids in the form of their methanesulfonates were administered into the jugular vein using a slow infusion apparatus (B. Melsungen) in doses of 0.15, 0.45 and 1.5 mg / kg body weight.

The results of the experiments show that clockwise Ergot alkaloids have no effect on blood pressure and pulse rate.

b) Effect on lowering blood pressure in spinal rats

Wistar rats under urethane anesthesia were spinalized (the

Spinal cord was severed in the area of the second cervical vertebra) and connected to a device for artificial respiration (B. Melsungen). The central blood pressure regulation was switched off by this intervention. The animals had a blood pressure drop of about 50 mm Hg. This experiment was used to determine whether the compounds examined had an immediate effect on the smooth muscles of the blood vessels.

The results of the tests have shown that acid addition salts of ergotaminin, ergocryptinin and ergocorninin in a dose of 1.5 mg / kg body weight cause long-term hypertension lasting more than 60 minutes. The same effect was only achieved with ergosinin at a dose of 4.5 mg / kg body weight; however, ergocristinine had no effect even at a dose of 4.5 mg / kg body weight.

The heart rate was reduced in the course of the experiment in all of the right-handed Ergot alkaloids mentioned, except for Ergocristinin.

The experiments above show that ergotaminin, ergocryptinin, ergosinin and ergocorninin, like dihydroergotoxin and dihydroergotamine, have a vasoconstrictive effect or that the contractions cause the smooth muscles of the blood vessels (Rothlin, E.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

641185

4th

and Cerletti, A., Verh. dtsch. Ges. Kreislaufforsch. 15, 1949, 158).

c) Effect on arterial pressure in spontaneously hyper-intensive rats

In this experiment groups of 10 spontaneously hypertensive Okamoto Aoki F32 rats of both sexes with a body weight of 200-250 g were used. The acid addition salts of the right-handed ergot alkaloids mentioned were administered intraperitoneally in doses of 50 mcg / kg body weight and the systolic blood pressure was determined using the plethysmographic method on the rat tail (Okamoto, K. and Aoki, K., Jap. S Circulât. J. 27 , 1963, 282).

The test results are summarized in Table II below.

Table II

Substance Systolic blood pressure in mm Hg

Day control 2 4 6 8 10

Ergotaminin methanesulfonate

189

162

143

131

144

150

Ergosinin methanesulfonate

180

169

152

140

141

138

Ergocryptinine methanesulfonate

189

181

176

168

161

160

Ergocristinin methanesulfonate

187

183

177

169

160

152

Ergocorninine methanesulfonate

190

182

176

166

160

161

Ergotamine tartrate

179

174

170

172

173

172

Ergosine methanesulfonate

188

183

178

176

175

177

The test results show that all of the right-handed Ergot alkaloids mentioned gradually lower the systolic blood pressure in spontaneously hypertensive rats. Ergosinin and ergotaminin have the strongest effects.

Most left-handed ergot alkaloids have no effect on systolic blood pressure in spontaneously hypertensive rats.

3. Effect on the heart

In experiments with normotensive anesthetized spinal rats, right-handed ergot alkaloids in effective doses cause a reduction in cardiac activity or bradycardia. This effect has been demonstrated for all known Ergot alkaloids or their derivatives, e.g. in the case of ergotoxin, ergotamine, dihydroergotoxin, dihydroergotamine and others, found (Rothlin, E., Vienna. Klin. Wschr. 62, 1950,893).

The effect of right-handed Ergot alkaloids according to the invention on the heart in vitro was investigated on the isolated heart of the guinea pig according to the modified Langendorff method (Zalar et al., Boll. Chim. Farmac. 114, 1975, 146). The alkaloids were infused using slow infusion equipment (B. Melsungen).

The results of the tests are summarized in Table III below.

Table III

Substance dose (+) inotropic (-) chrono- 55

(mcg / g (maximum) trop heart) in% (maximum)

in ° / o

The results show that ergotaminin, ergosinin and ergocryptinin have a qualitatively similar effect to ergotamine, ergosin and dihydroergotamine on isolated hearts.

Ergosinin and especially ergocryptinin have a quantitatively stronger effect on the contraction power of the heart.

The effect of ergotaminin, ergosinin and ergocristinin on the heart in situ was investigated in rats. The chest was opened in anesthetized (0.7 ml of a 25% urethane solution per 100 g body weight, subcutaneous) rats. The heart was placed in a special basket with a balloon connected via a polyethylene cannula with a "Mini Pressure Transducer - Beckmann" and a Beckmann dynograph. Since the left ventricular wall was leaning against the balloon, it was possible to register the ventricular contractions. The rats were connected to a device for artificial respiration via a tracheal tube.

The results showed that ergotaminin, ergosinin and ergocristinin in doses of 250 and 300 mcg / kg body weight i.v. (with an apparatus for slow infusion B. Melsungen) cause 15 or 30% stronger heart contractions.

4. Effect on the arrhythmia caused by adrenaline

It is known that left-handed ergot alkaloids and their derivatives completely or partially prevent the development of cardiac arrhythmias caused by adrenaline.

The experiments were carried out with guinea pigs of both sexes with a body weight of 400 to 550 g. The anesthetized (urethane, 1.6 g / kg body weight i.p.) animals were first given adrenaline (0.02 mg / kg body weight i.v.) and then right-handed ergot alkaloids. 1 and 1.5 hours after the application of right-handed Ergot alkaloids, adrenaline was applied again (0.02 mg / kg body weight i.v.) and the occurrence and duration of the arrhythmias were determined.

The test results are summarized in Table IV below.

Ergotaminin methanesulfonate

5.59

32

20th

Ergosinin methanesulfonate

0.65

103

23

Ergocryptinine methanesulfonate 0.04

111

21st

Ergocristinin methanesulfonate

4.98

9

12

Ergocorninine methanesulfonate

4.90

-

11

Ergotamine tartrate

0.65

75

30th

Ergosine methanesulfonate

0.57

49

17th

35

40

45

5

641185

Table IV

substance

Dose Reduction in the duration (mg / kg i.p.) of the arrhythmia in% of the control

Ergotaminin methanesulfonate

2.0

28

Ergosinin methanesulfonate

2.0

79

Ergocryptinine methanesulfonate 2.0

63

Ergocristinin methanesulfonate

2.0

32

Ergocorninine methanesulfonate

2.0

46

Ergotamine tartrate

2.0

63

Ergosine methanesulfonate

2.0

84

The above results show that the duration of the arrhythmia is most shortened by ergosinin, followed by ergocryptinin, ergocorninin, ergocristinin and ergotaminin. Left-handed Ergot alkaloids have a somewhat stronger antiarrhythmic or antiadrenaline effect.

5. Effect on pupil function

Mydriasis caused by Ergot alkaloids is the stimulation of the a-adrenergic receptors of the dictating pupil muscle (Votava Z, et al., Arch. Int. Pharmacodin 45, 1958, 114).

The mydriatic effect of the i.v. Right-handed ergot alkaloids were applied using a monocular magnifying glass according to the Polewkaschen method (Turner, A.R., Screening Methods in Pharmacology, 1965, pp. 174 ff.).

The pupil size was determined first before application of the substance and then 15.30 and 60 min after i.v. Application of the alkaloids in the mouse tail (dose 5 mg / kg body weight) measured.

The test results are summarized in Table V below.

Table V

Substance of pupil dilation in% compared to the control after 15 after 30 after 60 min. Min. Min.

Ergotaminin methanesulfonate

66.3

69.8

30.3

Ergosinin methanesulfonate

135.0

122.5

32.5

Ergocryptinine methanesulfonate 117.4

91.6

32.2

Ergocristinin methanesulfonate

48.7

10.3

2.5

Ergocorninine methanesulfonate

52.7

36.1

19.4

Ergotam i n tartrate

73.3

22.8

4.6

Ergosine methanesulfonate

115.6

110.5

39.7

From the above results, it can be seen that right-handed Ergot alkaloids produce a mydriatic effect that is similar to that of left-handed Ergot alkaloids. Ergosinin and ergocryptinin have the strongest mydriatic effect.

Based on the pharmacological properties, it was found that the right-hand rotating Ergot alkaloids according to the invention:

have a hypotensive effect, as can be seen from the experiments with spontaneously hypertensive rats,

influence the strength of the contraction of the heart chamber and the pulse rate, as can be seen from the experiments on the isolated guinea pig heart and the rat heart in situ,

have an antiarrhythmic effect, as can be seen from the experiments on guinea pigs with arrhythmias caused by adrenaline,

- have a spasmogenic effect, as can be seen from the experiments on spinal rats, and act agonistically on α-receptors, as the experiments on the mouse pupil show.

Because of these properties, the right-turning ergot alkaloids ergotaminin, ergosinin, ergocryptinin, ergocristinin and ergocorninin can be used to treat arterial hypertension, heart failure, cardiac arrhythmia and migraines.

The right-handed Ergot alkaloids mentioned in the form of their physiologically tolerable acid addition salts can be used as drugs for enteral and parenteral use. Customary inorganic or organic adjuvants are usually added to the preparation of pharmaceutical preparations. For tablets or coated tablets, e.g. Lactose, starch, talc, magnesium stearate and the like, for solutions and suspensions e.g. Water, alcohols, glycerin, vegetable oils and the like, for suppositories e.g. natural and hardened oils and waxes can be added. The preparations can also contain suitable preservatives, stabilizers, surface-active substances, solubilizers, sweeteners and colorants.

The suitable dose for the right-handed Ergot alkaloids according to the invention in the form of their physiologically tolerable acid addition salts is preferably 0.01 to 1.0 mg / kg body weight per day.

The invention is explained in more detail by the following, in no way restricting examples.

Example I

Ergocristinin methanesulfonate

1.25 g (0.05 mmol) of ergocristinin are dissolved in 25 ml of absolute ethanol, which contains 0.15 ml (2.31 mmol) of methanesulfonic acid. After clarification, the solution is slowly stirred in 350 ml abs. Poured diethyl ether. The salt which has separated out is filtered off and dried in vacuo. 1.40 g (96.4% of theory) of ergocristinine methanesulfonate, mp. 177-180 ° C., are obtained.

Example 2 Ergocorninine Methanesulfonate

1.50 g (2.67 mmol) of ergocorninin in 20 ml of abs. Ethanol, which contains 0.21 ml (2.93 mmol) of methanesulfonic acid, dissolved. The clear solution is stirred in 300 ml abs. Poured diethyl ether. The salt which has separated out is filtered off and dried in vacuo. 1.64 g (98.2% of theory) of ergocorninine methanesulfonate, mp. 178-179 ° C., are obtained.

Example 3 Ergocryptinin methanesulfonate 2.30 g (4 mmol) ergocryptinin are dissolved in 20 ml abs. Ethanol, which contains 0.3 ml (4.62 mmol) of methanesulfonic acid, dissolved. The clear solution is stirred in 300 ml abs. Poured diethyl ether. The salt which has separated out is filtered off and dried in vacuo. 2.5 g (97.6% of theory) of ergocryptinine methanesulfonate, mp. 174-175 ° C., are obtained.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

6S

641185

6

Example 4 Ergosinin Methanesulfonate

5.48 g (10 mmol) of ergosinin are absorbed in 60 ml. Ethanol, which contains 0.72 ml (11 mmol) of methanesulfonic acid, dissolved. The clear solution is abs in 600 ml. Poured diethyl ether. The salt which has separated out is filtered off and dried in vacuo. 6.05 g (98.7% of theory) of ergosinine methanesulfonate, mp. 190-192 ° C., are obtained.

Example 5 Ergotaminin methanesulfonate 1.25 g (2.15 mmol) ergotaminin in 53 ml abs. Ethanol, which contains 0.16 ml (2.46 mmol) of methanesulfonic acid, dissolved. The clear solution is stirred in 430 ml abs. Poured diethyl ether. The salt which has separated out is filtered off and dried in vacuo. 1.3 g (99.2% of theory) of ergotaminine methanesulfonate, mp. 184-187 ° C., are obtained.

Example 6 Ergotaminin ethanesulfonate

0.58 g (1 mmol) of ergotaminin are reacted with 0.12 g (1.1 mmol) of ethanesulfonic acid in the same manner as in Example 5 to give the addition salt. 0.63 g (91.3% of theory) of ergotaminin ethanesulfonate, mp. 171-173 ° C., are obtained.

Example 7 Ergotaminin Hydrochloride

0.58 g (1 mmol) of ergotaminin are concentrated with 0.16 ml (1.6 mmol). Hydrochloric acid converted to the addition salt in the same way as in Example 5. 0.59 g (95.1% of theory) of ergotaminine hydrochloride, mp. 205 ° C. (dec.) Are obtained.

Example 8 Ergotaminin trifluoroacetate

0.58 g (1 mmol) of ergotaminin are reacted with 0.13 g (1.14 mmol) of trifluoroacetic acid in the same way as in Example 5 to give the addition salt. 0.47 g (67.7% of theory) of ergotaminine trifluoroacetate, mp. 178-180 ° C., are obtained.

Example 9 Ergotaminin trichloroacetate

0.58 g (1 mmol) of ergotaminin are mixed with 0.18 g (1.1 mmol) of trichloroacetic acid in the same way as in Example 5

converted to the addition salt. 0.21 g (28.3% of theory) of ergotaminin trichloroacetate, mp. 238 ° C. (dec.) Are obtained.

Example 10

Tablets mg / tablet

Composition: 10 inventive active ingredient lactose starch talc

Tragacanth 15 magnesium stearate

30 218 27 13 10 2

together 300 mg

20th

Example 11

Capsules mg / capsule

Active ingredient 25 lactose according to the invention

20 280

together 300 mg

Example 12

Solution for injection

Weight in mg

Composition:

3s Active ingredient 1.00 according to the invention

Sodium carboxymethyl cellulose 1.50

Polyvinyl pyrrolidone 5.50

Lecithin 3.20

Benzyl alcohol 0.01

40 buffers q.s. Bidistilled water ad 1 ml together 1 ml

B

Claims (5)

641 185 1. Physiologically acceptable acid addition salts of ergotaminin, ergosinin, ergocryptinin, ergocristinin and ergocorninin. 2. A process for the preparation of physiologically tolerable acid addition salts of ergotaminin, ergosinin, ergocryptinin, ergocristinin and ergocorninin according to claim 1, characterized in that the right-turning ergot alkaloid in a solvent which is inert to the reaction participants, which is one mole of the right-turning ergot alkaloids mentioned Contains 1 to 1.7 mol of the desired inorganic or organic acid, dissolves and the acid addition salt is eliminated by adding a precipitation solvent. 2nd PATENT CLAIMS 3. The method according to claim 2, characterized in that the solvent which is inert towards the reactants is preferably an alkanol having 1 to 3 carbon atoms or a ketone having 3 to 6 carbon atoms. 4. The method according to claim 2, characterized in that an aliphatic ether having 4 to 8 carbon atoms is preferably used as the precipitation solvent. 5. Medicament for the treatment of arterial hypertension, heart failure, cardiac arrhythmia and migraine, characterized in that it contains a pharmacologically acceptable salt of ergotaminin, ergosinin, ergocryptinin, ergocristinin and ergocorninin according to claim 1.